PROJECT ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of liver disease present in approximately 80% of obese individuals. The factors leading to the development of liver fat and progression to nonalcoholic steatohepatitis (NASH), including inflammation and fibrosis, are poorly understood, and there is a clear unmet research need in this area given the lack of effective therapies. The proposed research is significant because it has the potential to elucidate poorly defined pathophysiologic mechanisms of this highly prevalent public health disease, and identify new therapeutic targets The scientific goal of this project is to elucidate the role of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of NAFLD and NASH. The central hypothesis is that relative GH and IGF-1 deficiency in obesity are associated with development and progression of NAFLD and NASH, and that GH administration will reduce steatosis, inflammation and fibrosis. Aim 1 will determine the relationship between the GH/IGF-1 axis and intrahepatic lipid content, inflammation and fibrosis. Aim 2 investigates the effect of low-dose GH vs. placebo on these endpoints in biopsy-proven NASH. The rationale for this proposal is that relative GH/IGF-1 deficiency in obesity may play a role in the development and progression of NAFLD and NASH given its lipolytic, anti-inflammatory and anti-fibrotic properties and based on our preliminary data. The candidate is an Instructor of Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital (MGH) who is highly qualified for and deeply committed to developing a career as an independent investigator. Her short-term goal is to develop the skills and obtain the preliminary data necessary to make the transition to her first R-level independent NIH grant-supported research. Her long- term goal is to become an independent, patient-oriented researcher in endocrine mechanisms that may contribute to the etiopathology of NAFLD and progression to NASH. She is supported by an expert and highly- invested mentorship team composed of successful, NIH-supported clinical investigators in Neuroendocrinology, Hepatology and Radiology and has an impressive track record of success, including awards, pilot grants and publications. She and her mentors have designed a targeted training plan consisting of co-mentorship and a didactic program. The institutional environment is outstanding at MGH and Harvard Medical School, with multiple resources available from the MGH Department of Medicine, the MGH Division of Clinical Research, and the Harvard Medical School Clinical Translational Science Center grant, all of which offer a myriad of didactic opportunities, facilities and support to the candidate. The Neuroendocrine Unit and Department of Medicine have made a strong commitment to the candidate, including 90% protected time, space, study coordinator support and a faculty appointment, with the goal of fostering the candidate's career as an independent investigator.